研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Anchorage-independent growth of mouse male germline stem cells in vitro. 査読有り

Shinohara M, Inoue K, Lee J, Miki H, Ogonuki N, Toyokuni S, Ogura A and Shinohara T.

Biol. Reprod. 74 巻頁： 522-529 2006年

An N-glycan structure correlates with pulmonary metastatic ability of cancer cells. 査読有り

Sakuma K, Fujimoto I, Hitoshi S, Tanaka F, Ikeda T, Tanabe K, Toyokuni S, Wada H, Mio T, Mishima M, Ikenaka K.

Biochem. Biophys. Res. Commun. 349 巻頁： 829-835 2006年

Novel aspects of oxidative stress-associated carcinogenesis. 査読有り

Toyokuni S.

Antiox. Redox Signal. 8 巻頁： 1373-1377 2006年

Involvement of aminoacylase 1 in ferric nitrilotriacetate (Fe-NTA)-induced rat renal cell carcinoma

Onuki, J; Liu, Y; Lee, W; Jiang, L; Dutta, KK; Akatsuka, S; Toyokuni, S

FREE RADICAL RESEARCH 40 巻頁： S128 - S128 2006年

Iron-Induced Carcinogenesis 査読有り国際誌

Toyokuni, S

OXIDATIVE STRESS, DISEASE AND CANCER 頁： 789 - 805 2006年

Novel aspects of oxidative stress-associated carcinogenesis

Toyokuni Shinya

ANTIOXIDANTS & REDOX SIGNALING 8 巻 ( 7-8 ) 頁： 1373 - 1377 2006年

酸化ストレスと癌国際誌

豊國伸哉

日本トキシコロジー学会学術年会 33 巻 ( 0 ) 頁： 15 - 15 2006年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

「フリーラジカル・活性酸素による負荷から、抗酸化分子・抗酸化酵素・修復酵素などを介した消去・防御・修復能を差し引いたもの」が酸化ストレスの概念である。ここでは、発がんおよびがん領域における酸化ストレス研究の現状ならびにどのようなアプローチが可能かに関して新旧併せて紹介する。私たちは、鉄キレート剤投与によりFenton反応を尿細管にひき起こす腎傷害・発がんモデルを詳細に検討してきた。通常のパラフィン包埋標本上で酸化ストレスの可視化が可能となったのは90年代になってからであった。フリーラジカル反応で特異的に発生しかつ標本内に固定される epitopeに対する抗体を作製がなされた。脂質過酸化最終産物の一つである4-hydroxy-2-nonenalがMichael付加反応で蛋白と反応したhemiacetal構造、DNA修飾塩基である8-hydroxy-2'-deoxyguanosineやacrolein-deoxyadenosineが代表的 epitope である。これらの方法は既に定法として酸化ストレス病態の解析に広く使用されている。フリーラジカルはその反応性の高さより近傍にある分子と反応するため、反応選択性は低いと考えられてきた。私たちは、上記腎がんモデルにおいてF1動物を使用して遺伝学的解析を行い、主な標的遺伝子のひとつがp16INK4A がん抑制遺伝子であることを見いだした。しかもその変化は初期に発生する。発がんにおいては選択という要素があるが、フリーラジカルの反応は生体内において、特異的な表現型となりうることが判明してきた。最後に、がん発生の起点であるゲノム情報の変化に関して私たちがoxygenomicsと呼ぶ新しいアプローチを紹介する。 参考文献：1. Toyokuni S. Pathol Int 49: 91, 1999. 2. Tanaka T et al. Oncogene 18, 3793, 1999. 3. Hiroyasu et al. 160: 419, 2002. 4. Dutta KK et al. Lab Invest 85: 768, 2005.

DOI： 10.14869/toxp.33.0.15.0

CiNii Research

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Molecular characteristics of ferric nitrilotriacetate-induced deletions and base substitutions in the kidney of gpt delta transgenic mice

Jiang, L; Zhong, Y; Akatsuka, S; Onuki, J; Masumura, K; Nohmi, T; Toyokuni, S

FREE RADICAL RESEARCH 40 巻頁： S128 - S128 2006年

Iron-Induced Carcinogenesis

Toyokuni Shinya

OXIDATIVE STRESS, DISEASE AND CANCER 頁： 789 - 805 2006年

Deletion and single nucleotide substitution at G:C are major mutations in the kidney of gpt delta transgenic mice after the Fenton reaction. 査読有り

Jiang L, Zhong Y, Akatsuka S, Liu Y-T, Dutta KK, Lee W-H, Onuki J, Masumura K, Nohmi T, Toyokuni S

Cancer Sci. 97 巻頁： 1159-1167 2006年

Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis Open Access

Akatsuka S., Aung T. T., Dutta K. K., Jiang L., Liu Y., Lee W., Onuki J., Shirase T., Naito Y., Yoshikawa T., Uchida K., Toyokuni S.

FREE RADICAL RESEARCH 40 巻頁： S129 - S129 2006年

Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis 査読有り Open Access

S. Akatsuka, T. T. Aung, K. K. Dutta, L. Jiang, Y. Liu, W. Lee, J. Onuki, T. Shirase, Y. Naito, T. Yoshikawa, K. Uchida, S. Toyokuni

FREE RADICAL RESEARCH 40 巻頁： S129 - S129 2006年

Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice Open Access

Naito Y., Uchiyama K., Akagiri S., Aoi W., Hasegawa G., Nakamura N., Kokura S., Yoshida N., Ichikawa H., Toyokuni S., Yoshikawa T.

Journal of Clinical Biochemistry and Nutrition 37 巻 ( 1 ) 頁： 29 - 37 2005年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Biochemistry and Nutrition

The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Leprdb/+Leprdb (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

DOI： 10.3164/jcbn.37.29

Scopus

CiNii Research

Susceptibility of actin to modification by 4-hydroxy-2-nonenal. 査読有り国際誌

Ozeki M, Miyagawa-Hayashino A, Akatsuka S, Shirase T, Lee WH, Uchida K, Toyokuni S

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 827 巻 ( 1 ) 頁： 119 - 26 2005年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

4-Hydroxy-2-nonenal (HNE), a major lipid peroxidation product, reacts with histidine, lysine or cysteine residues of proteins to form hemiacetal Michael adducts and thus interferes with the functions of the proteins. Here we undertook to identify HNE-modified proteins in the target organ of a ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis model with histidine-specific HNEJ-2 antibody. Immunoaffinity column separation and sequencing identified one of the major modified proteins as actin. To further explore the characteristics of actin as an HNE acceptor, we produced four novel monoclonal antibodies against HNE-modified keyhole limpet hemocyanin. All these antibodies (HNEJ-1, 3-5) recognized histidine adducts, but were different from HNEJ-2 in recognizing lysine and cysteine adducts to some extent. Actin, albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), metallothionein and superoxide dismutase were treated in vitro with HNE and evaluated with these antibodies. The results revealed that actin was most sensitive to HNE modification and metallothionein most resistant. Furthermore, the residue-specificity of GAPDH was in accord with that shown by our recent mass spectrometry data. Immunohistochemistry with the antibodies revealed cytoplasmic staining with or without nuclear staining in the renal proximal tubules after Fe-NTA administration. The results suggest that actin is a major target protein for HNE modification in vivo, and that our monoclonal antibodies are useful for evaluating the HNE adducts produced. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jchromb.2005.02.025

Susceptibility of actin to modification by 4-hydroxy-2-nonenal

OZEKI Munetaka, MIYAGAWA HAYASHINO Aya, AKATSUKA Shinya, SHIRASE Tomoyuki, LEE Wen-hua, UCHIDA Koji, TOYOKUNI Shinya

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 827 巻 ( 1 ) 頁： 119 - 126 2005年11月

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p35

Yajima N, Yamada S, Morisaki T, Toyokuni S, Yonehara S, Sakamaki K

TRANSGENIC RESEARCH 14 巻 ( 5 ) 頁： 593 - 604 2005年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Transgenic Research

Baculovirus p35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficent animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development. © Springer 2005.

DOI： 10.1007/s11248-005-4350-5

Web of Science

Scopus

PubMed

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p 35. 国際誌

Nobuyuki Yajima, Shu-Ichi Yamada, Takayuki Morisaki, Shinya Toyokuni, Shin Yonehara, Kazuhiro Sakamaki

Transgenic research 14 巻 ( 5 ) 頁： 593 - 604 2005年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Baculovirus p 35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p 35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficient animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p 35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p 35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development.

PubMed

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Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1. 国際誌 Open Access

Kawasaki K, Nishio A, Nakamura H, Uchida K, Fukui T, Ohana M, Yoshizawa H, Ohashi S, Tamaki H, Matsuura M, Asada M, Nishi T, Nakase H, Toyokuni S, Liu W, Yodoi J, Okazaki K, Chiba T

Laboratory investigation; a journal of technical methods and pathology 85 巻 ( 9 ) 頁： 1104 - 17 2005年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Laboratory Investigation

Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2′-deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1β and tumor necrosis factor-α gene expression in H. felis-infected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress. © 2005 USCAP, Inc All Rights Reserved.

DOI： 10.1038/labinvest.3700305

Germline niche transplantation restores fertility in infertile mice. 査読有り国際誌 Open Access

Kanatsu-Shinohara M, Miki H, Inoue K, Ogonuki N, Toyokuni S, Ogura A, Shinohara T

Human reproduction (Oxford, England) 20 巻 ( 9 ) 頁： 2376 - 82 2005年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Human Reproduction

Background: Stem cells interact closely with their microenvironment or niche, and abnormalities in niche compromise the self-renewing tissue. In testis, for example, Sertoli cells interact with germ cells, and defects in Sertoli cells compromises spermatogenesis, leading to male infertility. However, it has not been possible to restore spermatogenesis from endogenous stem cells in infertile testis with environmental defects. Methods and results: When healthy Sertoli cells from infertile white spotting (W) mouse were transplanted into the seminiferous tubules of infertile Steel (Sl) mouse testis that had defective Sertoli cells, spermatogenesis occurred from Sl stem cells in the recipient testis. On average, 1.1% of the recipient tubules showed spermatogenesis. Furthermore, in a microinsemination experiment with germ cells that developed in the testis, we obtained four normal offspring from 114 successfully injected oocytes. Conclusions: This study demonstrates that defects in male germline microenvironment can be corrected by Sertoli cell transplantation. Although further improvements are required to enhance the low efficiency of spermatogenesis, the ability to correct environmental defect by niche transplantation has important implications in developing new strategies for treating incurable disorders in self-renewing tissues. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

DOI： 10.1093/humrep/dei096

Genetic and epigenetic properties of mouse male germline stem cells during long-term culture. 査読有り国際誌

Kanatsu-Shinohara M, Ogonuki N, Iwano T, Lee J, Kazuki Y, Inoue K, Miki H, Takehashi M, Toyokuni S, Shinkai Y, Oshimura M, Ishino F, Ogura A, Shinohara T

Development (Cambridge, England) 132 巻 ( 18 ) 頁： 4155 - 63 2005年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Development

Although stem cells are believed to divide infinitely by self-renewal division, there is little evidence that demonstrates their infinite replicative potential. Spermatogonial stem cells are the founder cell population for spermatogenesis. Recently, in vitro culture of spermatogonial stem cells was described. Spermatogonial stem cells can be expanded in vitro in the presence of glial cell line-derived neurotrophic factor (GDNF), maintaining the capacity to produce spermatogenesis after transplantation into testis. Here, we examined the stability and proliferative capacity of spermatogonial stem cells using cultured cells. Spermatogonial stem cells were cultured over 2 years and achieved ∼1085-fold expansion. Unlike other germline cells that often acquire genetic and epigenetic changes in vitro, spermatogonial stem cells retained the euploid karyotype and androgenetic imprint during the 2-year experimental period, and produced normal spermatogenesis and fertile offspring. However, the telomeres in spermatogonial stem cells gradually shortened during culture, suggesting that they are not immortal. Nevertheless, the remarkable stability and proliferative potential of spermatogonial stem cells suggest that they have a unique machinery to prevent transmission of genetic and epigenetic damages to the offspring, and these characteristics make them an attractive target for germline modification.

DOI： 10.1242/dev.02004

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論文 - 豊國 伸哉

<豊國　伸哉>

論文 - 豊國　伸哉